Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones

Adams, Andrew C.; Coşkun, Tamer; Cheng, Christine; O’Farrell, Libbey; DuBois, Susan; Kharitonenkov, Alexei

doi:10.1016/j.molmet.2013.05.005

Cited by 70 publications

(61 citation statements)

References 46 publications

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“…As recently reported in mice fed a HFD or a ketogenic diet, deletion of Fgf21 elevated plasma insulin (36,48). In the present study, the HFD increased fasting plasma insulin in Fgf21 -/-mice by 7.5-fold, which was significantly greater than the 4-fold increase observed for HFD-fed WT mice, as compared to chow-fed controls ( Figure 7A).…”

Section: Naringenin Prevents Hyperinsulinemia and Improves Glucose Hosupporting

confidence: 78%

“…A similar difference in phenotype was observed upon feeding Fgf21 -/-mice either a chow, ketogenic diet or a HFD, although the adipose tissue increases were more modest (36,41,48). However, a third strain of Fgf21 -/-mice fed a HFD were reported to be leaner as compared to WT mice (56), and the reasons for this discrepancy are currently unknown (56).…”

Section: Discussionmentioning

confidence: 63%

“…The most prominent phenotype in HFD-fed Fgf21 -/-mice was enhanced weight gain (170%) and adiposity in both visceral (200%) and subcutaneous (180%) fat depots, compared to HFD-fed WT controls, despite no difference in caloric consumption (36,48). A similar difference in phenotype was observed upon feeding Fgf21 -/-mice either a chow, ketogenic diet or a HFD, although the adipose tissue increases were more modest (36,41,48).…”

Section: Discussionmentioning

confidence: 69%

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Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

et al. 2015

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The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21(-/-) mice. HFD-fed Fgf21(-/-) mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo.

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Section: Naringenin Prevents Hyperinsulinemia and Improves Glucose Hosupporting

confidence: 78%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 69%

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Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

et al. 2015

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“…Ligand activation of PPAR␥ acted in the opposite direction, inducing the transcription of Klb and its eRNAs. KLB was also found to be up-regulated in EWAT of mice treated with PPAR␥ ligands (58,59). Moreover, knockdown of PPAR␥ led to a decrease in KLB mRNA level in 3T3-L1 adipocytes.…”

Section: Discussionmentioning

confidence: 88%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

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FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb␣, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb␣ for Rev-erb␣-binding sites identified ␤Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb␣ in white adipose tissue but not liver. Rev-erb␣ ablation led to the robust elevated expression of ␤Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Reverb␣. A major Rev-erb␣-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ␥, which regulates its activity in the opposite direction. These findings establish Rev-erb␣ as a specific modulator of FGF21 signaling in adipose tissue.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

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“…While the metabolic effects of FGF21 deletion on diet-induced obesity models were variable [33,34], FGF21 deletion exacerbated hepatic ER stress and worsened glucose tolerance/insulin resistance in ob mice. However, alterations of these metabolic variables were not associated with beta cell failure.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress

Kim

et al. 2014

Diabetologia

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Aims/hypothesis Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity.Methods Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. Results We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinaseeukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. Conclusions/interpretation Our results suggest that FGF21 plays an important role in the adaptive response to ER stress-or obesity-induced hepatic metabolic stress.

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Fibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones

Cited by 70 publications

References 46 publications

Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress

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